Modulation of Electromechanical Coupling as the Primary Mechanism for PIP2 and KCNE1 Regulation of Kv7.1 Channel Gating
Date of Award
Doctor of Philosophy (PhD)
Voltage-gated ion channels are an important class of transmembrane proteins. Expressed widely throughout the body, they play a central role in many physiological processes by generating the dynamic electric currents underlying the action potential waveforms. Action potentials coordinate contraction of muscular tissues, encode information in the nervous system, and stimulate neurohormonal release. The significance of voltage-gated ion channels to human health is demonstrated by a set of rare diseases for which inherited ion channel dysfunction has been identified as the primary pathogenic mechanism. Furthermore, as a major transmembrane signaling pathway, these channels are important therapeutic targets for many disease-states, including the monogenic channelopathies and other more complex diseases. For these reasons, exhaustive basic research into the structure and function of voltage-gated ion channels has, and continues to be, rationalized. The voltage-gated ion channel structure consists of four voltage-sensing domains (VSDs) surrounding a central pore-gate domain (PD). Its basic functions include sensing of transmembrane electric potential and opening/closing a pore through which selected ions can cross the membrane. As their name suggest, voltage-sensing occurs in the VSD, and the PD contains the gated ion permeation pathway. Voltage-sensing and pore-gate opening have been described in great molecular and biophysical detail; however, the mechanisms through which the VSD and PD interact to couple their functions remains poorly defined. In this work, I developed a conceptual and experimental framework that allows VSD-PD coupling to explicitly defined and experimentally detected. Applying these techniques, I studied the voltage-dependent gating of Kv7.1 potassium channels and its regulation by phosphatidylinositol 4,5-bisphosphate (PIP2), a membrane lipid, and KCNE1, a small transmembrane peptide. Addressing two longstanding mysteries in the field, I found that direct modulation of VSD-PD coupling is the primary mechanism through which PIP2 and KCNE1 affect the gating of Kv7.1. This work has direct relevance to cardiac electrophysiology because channels formed by Kv7.1 and KCNE1 generate a voltage- and PIP2-dependent current, IKs, that plays a critical role in limiting the duration of the cardiac action potential duration. The work reported in this thesis offers new insights into how mutations of Kv7.1 or KCNE1 alter the properties of IKs and predispose patients to sudden cardiac death.
Jianmin Colin . Cui Nichols
Gustav Akk, Jianmin Cui, Jeanne M. Nerbonne, Colin G. Nichols,
Available for download on Friday, May 15, 2116
Permanent URL: https://doi.org/10.7936/K7319T53